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Function and Gene Expression of Islets Experimentally Transplanted to Muscle or Omentum
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Transplantation och regenerativ medicin.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Transplantation och regenerativ medicin.ORCID-id: 0000-0003-4804-5091
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.ORCID-id: 0000-0002-8302-3253
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
Visa övriga samt affilieringar
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nyckelord [en]
Islet transplantation, muscle, omentum, engraftment, gene expression, laser capture microdissection
Nationell ämneskategori
Cell- och molekylärbiologi
Forskningsämne
Medicinsk cellbiologi
Identifikatorer
URN: urn:nbn:se:uu:diva-282952OAI: oai:DiVA.org:uu-282952DiVA, id: diva2:917915
Tillgänglig från: 2016-04-08 Skapad: 2016-04-08 Senast uppdaterad: 2020-01-17
Ingår i avhandling
1. Engraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell Mass
Öppna denna publikation i ny flik eller fönster >>Engraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell Mass
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Islet transplantation is a possible curative treatment for type 1 diabetes (T1D). Currently the liver dominates as implantation site, despite the many challenges encountered at this site.

Acute hypoxia in islets transplanted to muscle and omentum, two possible alternative sites, was prevailing. However, it was rapidly reversed at both implantation sites, in contrast to when islets were transplanted intraportally. At the intramuscular site hypoxia was further relieved by co-transplantation of an oxygen carrier, polymerized hemoglobin, which also improved the functional outcome. The complement system was activated after islet transplantation to muscle, but did not hamper graft function.

Both mouse and human islets transplanted to omentum become well re-vascularized and have a functional blood flow and oxygenation comparable with that of endogenous islets. Animals transplanted with islets to the omentum had a superior graft function compared with animals receiving intraportal islet grafts.

Alloxan-diabetic animals were cured with a low number of islets both when the islets were implanted in the omentum and muscle. The islet grafts responded adequately to both glucose and insulin and displayed a favorable mRNA gene expression profile.

A challenge in diabetes research and in islet transplantation is that there are no established techniques for quantifying beta-cell mass in vivo. By using radiolabeled Exendin-4, a GLP-1 receptor agonist, beta-cell mass after transplantation to muscle of mice was quantified. The results may well be translated to the clinical setting.

By comparing the pancreatic accumulation of [11C]5-hydroxy tryptophan ([11C]5-HTP) as detected by positron emission tomography (PET) in T1D patients with that of healthy controls, a 66% decrease was observed. This may in fact represent the loss of beta-cells, taking into account that other cells within the islets of Langerhans are largely unaffected in T1D. 

In conclusion, the data presented support the use of alternative implantation sites for islet transplantation. In addition to improving the functional outcome this may enable more transplantations since the number of transplanted islets may be reduced. The techniques investigated for quantifying transplanted and endogenous beta-cell mass may greatly improve our knowledge of the pathophysiology of T1D and become a valuable tool for evaluation of beta-cell mass.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2016. s. 88
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1211
Nyckelord
Type 1 diabetes, Islet transplantation, Alternative implantation sites, Exendin-4, Positron Emission Tomography, 5-hydroxy tryptophan, Beta-cell mass
Nationell ämneskategori
Cell- och molekylärbiologi
Forskningsämne
Medicinsk cellbiologi
Identifikatorer
urn:nbn:se:uu:diva-282953 (URN)978-91-554-9551-0 (ISBN)
Disputation
2016-06-01, Sal B22, BMC, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-05-11 Skapad: 2016-04-08 Senast uppdaterad: 2018-01-10
2. Challenges in Islet Transplantation and Strategies to Improve Beta-Cell Function
Öppna denna publikation i ny flik eller fönster >>Challenges in Islet Transplantation and Strategies to Improve Beta-Cell Function
2020 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The incidence of type 1 diabetes is increasing worldwide and therapies of islet transplantation and potential cell-based therapies are rapidly evolving. Choosing the optimal site for such therapies is crucial for safety and for obtaining the best possible outcome. The liver is currently the site of choice, but is unfortunately associated with disadvantages for graft survival.

In paper I, intraportally transplanted human islets were evaluated for hypoxia, apoptosis, and beta-cell survival. This revealed a substantial graft loss of approximately 50 % of transplanted islet mass at one month posttransplantation. At the same time, revascularization was increased, yet still lower than that of native islets. The highest rate of apoptosis was associated with prolonged time in culture prior transplantation.

Due to progressive loss of graft function, repeated islet transplantation is often performed. A mouse model, used in paper II, demonstrated an increased survival rate of islets transplanted one week after a first transplant. This finding may reflect an improved engraftment environment “primed” by the first islet injection. No difference in islet vascular density could be ascribed to it.   

As stem cell-based therapies improve, graft monitoring possibilities and retrieval are of importance for safely introducing these techniques into the clinic. Islet grafts to omentum and muscle cured diabetic mice in paper III. Gene expression was unaltered or increased for genes important for beta-cell function.

Decidual stromal cells (DSCs) have immunomodulatory properties that could prove useful for treatments of autoimmune or inflammatory conditions. In paper IV, DSCs were found to be easily isolated from human placenta. The cells were characterized by surface markers, differentiation capacity and gene expression during culture. Co-culture with human pancreatic islets was also conducted. DSCs were observed to be very similar to other types of mesenchymal stromal cells. Greatest change in gene expression was seen between passage 2 and 5. The effect on human islet function may depend on islet viability prior to co-culture.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2020. s. 52
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1633
Nyckelord
Islet transplantation, Type 1 diabetes, Mesenchymal stem cells
Nationell ämneskategori
Cell- och molekylärbiologi
Forskningsämne
Medicinsk cellbiologi
Identifikatorer
urn:nbn:se:uu:diva-402501 (URN)978-91-513-0858-6 (ISBN)
Disputation
2020-03-06, Room B22, BMC, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2020-02-14 Skapad: 2020-01-17 Senast uppdaterad: 2020-02-14

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